Secretion of anterior pituitary hormones undergoes feedback control by peripheral hormones secreted from target organs of the respective hormones and by secretion-regulating hormones from the hypothalamus, which is the upper central organ of the anterior lobe of the pituitary (hereinafter, these hormones are collectively called “hypothalamic hormones” in this specification). So far, the existence of nine kinds of hypothalamic hormones including, for example, thyrotropin releasing hormone (TRH), gonadotropin releasing hormone [GnRH, sometimes called LH-RH (luteinizing hormone releasing hormone)] and the like has been confirmed. These hypothalamic hormones are believed to show their actions via the receptors which are considered to exist in the anterior lobe of the pituitary, and analysis of the receptor-gene specific to these hormones, including for humans, has been made. Accordingly, antagonists or agonists specifically and selectively acting on these receptors should control the action of the hypothalamic hormone and the secretion of anterior pituitary hormone. As a result, such antagonists or agonists are expected to be useful in preventing or treating anterior pituitary hormone-dependent diseases.
Known compounds possessing GnRH-antagonizing activity include GnRH-derived linear peptides (U.S. Pat. Nos. 5,140,009 and 5,171,835), a cyclic hexapeptide derivative (JP-A-61-191698), a bicyclic peptide derivative [Journal of Medicinal Chemistry, Vol. 36, pp. 3265-3273 (1993)] and the like. Non-peptide compounds possessing GnRH-antagonizing activity include compounds described in WO 95/28405 (JP-A-8-295693), WO 96/24597 (JP-A-9-169768), WO 97/14682 (JP-A-9-169735), WO 97/14697 (JP-A-9-169767), WO 99/33831 (JP-A-11-315079), WO 00/00493 (JP-A-2000-219691), WO 00/56739 (JP-A-2001-278884) and JP-A-2002-30087 etc.
Peptide compounds have many problems to be resolved with respect to oral absorbability, dosage form, dose volume, drug stability, duration of action, stability to metabolism and the like. There is a strong demand for a GnRH antagonist, especially one based on a non-peptide compound, that has excellent therapeutic effect on hormone-dependent cancers, e.g., prostatic cancer, endometriosis, precocious puberty and the like, and further that does not show transient pituitary-gonadotropic action (acute action) and that has excellent oral absorption.